The present invention provides for a novel method of treating polycystic ovary syndrome. Further, the present invention is directed to a method of improving fertility and the response to in vitro fertilization (I.V.F.) by employing a 5xcex1-reductase type 1 inhibitor. The present invention also provides for a method of manufacture of a medicament useful for treating polycystic ovary syndrome and a method of manufacture of a medicament useful as an adjunct in I.V.F. The present invention also provides for compositions useful in the method of treating polycystic ovary syndrome and useful as an adjunct in I.V.F.
Polycystic ovary syndrome (PCOS), also known as Stein-Leventhal syndrome, is characterized by menstrual irregularity and hirsutism and is a common cause of anovulatory infertility. The biochemical abnormalities are a high concentration of plasma luteinising hormone (LH) or a high LH/follicle stimulating hormone (FSH) ratio and high concentrations of androgens (testosterone and/or androstenedione and/or dehydroepiandrosterone (DHEA)). The increased androgens can be secreted by the ovary and/or the adrenal gland. Clinical manifestations of PCOS include amenorrhea, hirsutism acanthosis nigricans, acne and obesity. PCOS appears to account for about 75% of anovulatory infertility.
The chronic anovulation typical of PCOS results in an increased number of atretic follicles (which become cysts) and increased interstitial tissue in the stroma of the ovaries.
Under normal conditions, women produce a single dominant follicle that participates in a single ovulation each menstrual cycle. The process begins when a cohort of primordial follicles is recruited to initiate growth. Successive recruitment gives rise to the primary, secondary, tertiary and graafian follicles present in the ovaries. The ability to become a dominant follicle is not a characteristic shared by all follicles, and those that lack the property die by atresia due to increased androgens. In the human female, only about 400 of the original 7 million follicles survive atresia and give rise to dominant follicles.
In patients with PCOS, the process of folliculogenesis does not proceed normally. The initial steps, recruitment and growth to the small graafian stages, are functioning in PCOS, but the terminal step, the selection of dominant follicles that can ovulate, does not occur regularly. Viable follicles seldom develop beyond about the 6 mm stage. In some unexplained way, this condition leads to the accumulation of large numbers of small graafian follicles (commonly referred to as cysts) in which the theca interstitial cells (TIC) produce abnormally large amounts of androgen, but the granulosa cells (GC) fail to express the aromatase enzyme and aromatize the androgen substrate to estradiol. Consequently, a state of continued hyperandrogenism results. The problem is self-perpetuating in part because the atretic follicle becomes an androgenic follicle by a xe2x80x9cdefaultxe2x80x9d mechanism: because of low aromatase activity in atretic follicles, androstenedione is preferentially metabolized to testosterone and thence to dihydrotestosterone within the ovary.
The human ovarian stromal, thecal and granulosa cell compartments each contain 5xcex1-reductase activity. In the rat the 5xcex1-reduced androgens 5xcex1-androstane-3,17-dione (5xcex1-A) and dihyrotestosterone (DHT) are competitive inhibitors of aromatase activity. This is likely to occur in humans as well, and therefore the 5xcex1-reduced metabolites may lead to decreased aromatase activity, increased androgen secretion and follicular atresia.
Agarwal et al. xe2x80x9cA Mechanism for the Suppression of Estrogen Production in Polycystic Ovary Syndromexe2x80x9d J. Clin Endocrinology and Metabolism 81(10):3686-3691 (1996), propose that polycystic ovary syndrome follicular fluid contains abnormally high 5xcex1-A and/or DHT concentration that can inhibit aromatase activity. They conclude that 5xcex1-A is the primary inhibitor of aromatase activity in PCOS follicular fluid.
Stewart et al. xe2x80x9c5xcex1-reductase adtivity in polycystic ovary syndromexe2x80x9d The Lancet 335:431-433 (1990) investigated the hypothesis that in PCOS increased cortisol metabolism stimulates corticotropin-mediated androgen excess. They proposed that enhanced activity of 5xcex1-reductase is the fundamental defect in many patients with PCOS. The enzyme abnormality is proposed to mediate both hirsutism and enhanced hepatic cortisol metabolism. A concomitant increase in corticotropin secretion in women with PCOS is hypothesized to keep plasma cortisol concentrations normal, but at the expense of androgen excess. This hypothesis likely provides another mechanism, via the adrenal, in which the 5xcex1-reductase activity contributes to PCOS.
Presently polycystic ovary syndrome is treated with GnRH analogues, oral contraceptives, steroids (such as prednisone) and/or antiandrogens. These antagonize androgens or decrease the whole H-P-G or H-P-Adrenal axes. None of the treatments currently employed corrects the underlying problem of the hyperandrogenic production by the ovarian follicles. Further, each of the currently employed treatments has significant side effects including: hypoestrogenism (GnRH analogues), menstrual irregularity (spironolactone, an antiandrogen), and headaches, bloating and the rare occurrence of blood clots associated with oral contraceptives. Steroids also have significant side effects such as adrenal suppression, obesity, striae, hypertension, etc.
The present invention relates to methods of treating polycystic ovary syndrome. Further, the present invention is directed to a method of improving fertility and the response to in vitro fertilization (I.V.F.) by employing a 5xcex1-reductase type 1 inhibitor. It has now been found that a 5xcex1-reductase type 1 inhibitors of structural formula I: 
are useful for the treatment of polycystic ovary syndrome and for improving fertility and the response to in vitro fertilization.
The enzyme 5xcex1-reductase catalyzes the reduction of several androgens including: testosterone (T) to the more potent androgen, 5xcex1-dihydrotestosterone (dihydrotestosteronexe2x80x9d or DHT), as shown below: 
5xcex1-reductase also catalyzes the reduction of androstenedione (A) to androstanedione (5xcex1-A), as shown below: 
and the reduction of progesterone to dihydroprogesterone, as shown below: 
There are two isozymes of 5xcex1-reductase in humans. Andersson, et al., Proc. Natl. Acad. Sci. USA, 87:3640-44 (1990); Andersson, et al., Nature, 354, 159-61 (1991). The isozymes, usually called Type 1 and Type 2, exhibit differences in their biochemical properties, genetics, and pharmacology. Both isozymes are now the subject of considerable research and it has been found one isozyme (type 1) predominates in the sebaceous glands of facial skin and skin tissue and that the other (type 2) predominates in the prostate.
Finasteride (17xcex2-(N-tert-butylcarbamoyl)-3-oxo-4-aza-5xcex1-androst-1-en-3-one) as shown below, is a potent inhibitor of the human type 2 enzyme. 
Under the tradename PROSCAR(copyright), finasteride is known to be useful in the treatment of hyperandrogenic conditions, see e.g., U.S. Pat. No. 4,760,071. Finasteride is currently prescribed for the treatment of benign prostatic hyperplasia (BPH), a condition affecting to some degree the majority of men over age 55. Finasteride""s usefulness in the treatment of androgenic alopecia and prostatic cancer is described in the following documents: EP 0 285 382, published Oct. 5, 1988, EP 0 285 383, published Oct. 5, 1988 and Canadian patents 1,302,277 and 1,302,276.
There have been reports (e.g., Ciotta et al., Fertility and Sterility 64(2): 299-306,1996 and Fruzetti et al., J. Clin. Endocrin. Metab. 79: 703-706, 1994) in the literature of administration of the type 2 inhibitor finasteride to women with hirsutism, with no observed menstrual changes. Further, it has been reported that women with type 2 5xcex1-reductase deficiency have normal menstrual cycles. This suggests that the type 2 enzyme does not predominate in the ovary.
Haning, Jr., et al., J. Steroid Molec. Biol. 59(2): 199-204 (1996) have recently reported that the human ovary apparently expresses mRNA for 5xcex1-reductase type 1.
It has been presently found that the type 1 5xcex1-reductase inhibitors of the present invention are useful in the treatment of polycystic ovary syndrome and in improving fertility and the response to in vitro fertilization.
The present invention provides for a method of treating polycystic ovary syndrome in a subject in need of such treatment comprising the administration of a therapeutically effective amount of a compound of structural formula I: 
to the subject. The present invention further provides for a method for improving fertility and the response to in vitro fertilization (I.V.F.), comprising administration of therapeutically effective amount of compound of structural formula I to the subject. Further, the present invention provides for compositions useful in the methods of the present invention, as well as a method of manufacture of a medicament useful for treating polycystic ovary syndrome or for improving fertility and the response to in vitro fertilization (I.V.F.).
In one embodiment, the present invention is directed to a method for treating polycystic ovary syndrome in a subject in need thereof by administering to the subject an effective amount of a compound of structural formula I: 
or a pharmaceutically acceptable salt or ester thereof wherein:
the C1-C2 carbon-carbon bond may be a single bond, or a double bond as indicated by the dashed line;
R1 is selected from the group consisting of hydrogen and C1-10 alkyl;
R2 is selected from the group consisting of hydrogen and C1-10 alkyl; one of R3 and R4 is selected from the group consisting of hydrogen and methyl, and the other is selected from the group consisting of:
(a) amino;
(b) cyano;
(c) fluoro;
(d) methyl;
(e) OH;
(f) xe2x80x94C(O)NRbRc, where Rb and Rc are independently H, C1-6 alkyl, aryl, or arylC1-6 alkyl; wherein the alkyl moiety can be substituted with 1-3 of: halo; C1-4 alkoxy; or trifluoromethyl; and the aryl moiety can be substituted with 1-3 of: halo; C1-4 alkyl; C1-4 alkoxy; or trifluoromethyl;
(g) C1-10 alkyl-Xxe2x80x94;
(h) C2-10 alkenyl-Xxe2x80x94;
wherein the C1-10 alkyl in (g) and C2-10 alkenyl in (h) can be unsubstituted or substituted with one to three of:
i) halo; hydroxy; cyano; nitro; mono-, di- or trihalomethyl; oxo; hydroxysulfonyl; carboxy;
ii) hydroxyC1-6 alkyl; C1-6 alkyloxy; C1-6 alkylthio; C1-6 alkylsulfonyl; C1-6 alkyloxycarbonyl; in which the C1-6 alkyl moiety can be further substituted with 1-3 of: halo; C1-4 alkoxy; or trifluoromethyl;
iii) arylthio; aryl; aryloxy; arylsulfonyl;
aryloxycarbonyl; in which the aryl moiety can be further substituted with 1-3 of: halo; C1-4 alkyl; C1-4 alkoxy; or trifluoromethyl;
iv) xe2x80x94C(O)NRbRc; xe2x80x94N(Rb)xe2x80x94C(O)xe2x80x94Rc; xe2x80x94NRbRc; where Rb and Rc are defined above;
(i) aryl-Xxe2x80x94;
(j) heteroaryl-Xxe2x80x94, wherein heteroaryl is a 5, 6 or 7 membered heteroaromatic ring containing at least one member selected from the group consisting of: one ring oxygen atom, one ring sulfur atom, 1-4 ring nitrogen atoms, or combinations thereof, in which the heteroaromatic ring can also be fused with one benzo or heteroaromatic ring; wherein the aryl in (i) and heteroaryl in (j) can be unsubstituted or substituted with one to three of:
v) halo; hydroxy; cyano; nitro; mono-, di- or trihalomethyl; mono-, di- or trihalomethoxy; C2-6 alkenyl; C3-6 cycloalkyl; formyl; hydrosulfonyl; carboxy; ureido;
vi) C1-6 alkyl; hydroxy C1-6 alkyl; C1-6 alkyloxy; C1-6 alkyloxy C1-6 alkyl; C1-6 alkylcarbonyl; C1-6 alkylsulfonyl; C1-6 alkylthio; C1-6 alkylsulfinyl; C1-6 alkylsulfonamido; C1-6 alkylarylsulfonamido; C1-6 alkyloxy-carbonyl; C1-6 alkyloxycarbonyl C1-6 alkyl; RbRcNxe2x80x94C(O)xe2x80x94C1-6 alkyl; C1-6 alkanoylamino C1-6 alkyl; aroylamino C1-6 alkyl; wherein the C1-6 alkyl moiety can be substituted with 1-3 of: halo; C1-4 alkoxy; or trifluoromethyl;
vii) aryl; aryloxy; arylcarbonyl; arylthio; arylsulfonyl; arylsulfinyl; arylsulfonamido; aryloxycarbonyl; wherein the aryl moiety can be substituted with 1-3 of: halo; C1-4 alkyl; C1-4 alkoxy; or trifluoromethyl;
viii) xe2x80x94C(O)NRbRc; xe2x80x94Oxe2x80x94C(O)xe2x80x94NRbRc; xe2x80x94N(Rb)xe2x80x94C(O)xe2x80x94Rc; xe2x80x94NRbRc; Rbxe2x80x94C(O)xe2x80x94N(Rc)xe2x80x94; where Rb and Rc are defined in (f) above; and xe2x80x94N(Rb)xe2x80x94C(O)xe2x80x94ORg, wherein Rg is C1-6 alkyl or aryl, in which the alkyl moiety can be substituted with 1-3 of: halo; C1-4 alkoxy; or trifluoromethyl, and the aryl moiety can be substituted with 1-3 of: halo; C1-4 alkyl; C1-4 alkoxy, or trifluoromethyl; xe2x80x94N(Rb)xe2x80x94C(O)NRcRd, wherein Rd is selected from H, C1-6 alkyl, and aryl; in which said C1-6 alkyl and aryl can be substituted as described above in (f) for Rb and Rc;
ix) a heterocyclic group, which is a 5, 6 or 7 membered ring, containing at least one member selected from the group consisting of: one ring oxygen atom, one ring sulfur atom, 1-4 ring nitrogen atoms, or combinations thereof; in which the heterocyclic ring can be aromatic, unsaturated, or saturated, wherein the heterocyclic ring can be fused with a benzo ring, and
wherein said heterocyclic ring can be substituted with one to three substituents, as defined above for v), vi), vii) and viii), excluding ix) a heterocyclic group; and
(k) R3 and R4 taken together can be carbonyl oxygen;
(l) R3 and R4 taken together can be xe2x95x90CHxe2x80x94Rg, wherein Rg is defined in viii); and wherein:
X is selected from the group consisting of:
xe2x80x94Oxe2x80x94; xe2x80x94S(O)nxe2x80x94; xe2x80x94C(O)xe2x80x94; xe2x80x94CH(Re)xe2x80x94; xe2x80x94C(O)xe2x80x94Oxe2x80x94*; xe2x80x94C(O)xe2x80x94N(Re)xe2x80x94*; xe2x80x94N(Re)xe2x80x94C(O)xe2x80x94Oxe2x80x94*; xe2x80x94Oxe2x80x94C(O)xe2x80x94N(Re)xe2x80x94*; xe2x80x94N(Re)C(O)xe2x80x94N(Re)xe2x80x94; xe2x80x94Oxe2x80x94CH(Re)xe2x80x94*; xe2x80x94N(Re)xe2x80x94; wherein Re is H, C1-3 alkyl, aryl, aryl-C1-3 alkyl, or unsubstituted or substituted heteroaryl, as defined above in (j);
wherein the asterisk (*) denotes the bond which is attached to the 16-position in Structure I; and n is zero, 1 or 2.
Still a further aspect of the present invention is a method of improving fertility and the response to in vitro fertilization (I.V.F.), in a subject in need thereof by administering an effective amount of a compound of structural formula I to the subject. The compounds of the present invention may provide a useful adjunct for in vitro fertilization because they may lead to multiple ovarian follicles developing completely through ovulation.
Another aspect of the present invention is the use of a compound of structural formula I for the manufacture of a medicament useful to treat polycystic ovary syndrome in a subject in need thereof. Still a further aspect of the present invention is the use of a compound of structural formula I for the manufacture of a medicament useful to improve fertility and the response to in vitro fertilization in a subject in need thereof.
In one embodiment of the present invention compounds of structural Formula I wherein R1 is hydrogen or methyl.
In another embodiment of the present invention, R2 is hydrogen or methyl.
A further embodiment of the present invention employs compounds of Formula I wherein:
one of R3 and R4 is selected from the group consisting of hydrogen and methyl, and the other is selected from the group consisting of:
(b) cyano;
(c) fluoro;
(e) OH;
(g) C1-10 alkyl-Xxe2x80x94; or C1-10 alkyl-Xxe2x80x94, where alkyl can be substituted with aryl, and wherein aryl in turn can be substituted with 1-2 of halo or C1-6 alkyl;
(h) C2-10 alkenyl-X;
(i) aryl-Xxe2x80x94;
(j) heteroaryl-Xxe2x80x94, wherein heteroaryl is a 5 or 6 membered heteroaromatic ring containing 1-2 ring nitrogen atoms; wherein the aryl in (i) and heteroaryl in (j) can be unsubstituted or substituted with one to two of:
x) halo; cyano; nitro; trihalomethyl; trihalomethoxy; C1-6 alkyl; aryl; C1-6 alkylsulfonyl; C1-6 alkyl-arylsulfonamino;
xi) xe2x80x94NRbRc; Rbxe2x80x94C(O)xe2x80x94N(Rc)xe2x80x94; wherein Rb and Rc are independently H, C1-6 alkyl, aryl, or arylC1-6 alkyl; wherein the alkyl moiety can be substituted with 1-3 of: halo; C1-4 alkoxy; or trifluoromethyl; and the aryl moiety can be substituted with 1-3 of: halo; C1-4 alkyl; C1-4 alkoxy; or trifluoromethyl;
xii) a heterocyclic group, which is a 5 membered aromatic ring, containing one ring nitrogen atom, or one ring oxygen and one ring nitrogen atom; and
(k) wherein R3 and R4 taken together can be carbonyl oxygen.
In a further embodiment of the present invention, X is selected from the group consisting of:
xe2x80x94Oxe2x80x94; xe2x80x94S(O)nxe2x80x94; xe2x80x94CH(Re)xe2x80x94; xe2x80x94C(O)xe2x80x94N(Re)xe2x80x94*; xe2x80x94Oxe2x80x94C(O)xe2x80x94N(Re)xe2x80x94*;
wherein the asterisk (*) denotes the bond which is attached to the 16-position in Structure I; and n is zero or 2.
In another embodiment of the present invention, Re is H, C1-3 alkyl, aryl, or aryl C1-3 alkyl.
Compounds of Formula I which may be employed in the present invention include but are not limited to the following:
4-aza-4,7xcex2-dimethyl-5xcex1-androstane-3,16-dione;
4-aza-4-methyl-5xcex1-androstan-3,16-dione;
3-oxo-4-aza-4-methyl-16xcex2-hydroxy-5xcex1-androstane;
3-oxo-4-aza-4-methyl-16xcex2-(benzylaminocarbonyloxy)-5xcex1-androstane;
3-oxo-4-aza-4-methyl-16-benzoylamino-5xcex1-androstane;
3-oxo-4-aza-4-methyl-16-methoxy-5xcex1-androstane;
3-oxo-4-aza-4-methyl-16xcex2-allyloxy-5xcex1-androstane;
3-oxo-4-aza-4-methyl-16xcex2-(n-propyloxy)-5xcex1-androstane;
3-oxo-4-aza-4-methyl-16xcex1-hydroxy-5xcex1-androstane;
3-oxo-4-aza-4-methyl-16xcex2-(phenoxy)-5xcex1-androstane;
3-oxo-4-aza-7xcex2-methyl-16xcex2-(phenoxy)-5xcex1-androst-1-ene;
3-oxo-4-aza-4-methyl-16xcex1-methoxy-5xcex1-androstane;
3-oxo-4-aza-4-methyl-16xcex2-(4-chlorophenoxy)-5xcex1-androstane;
3-oxo-4-aza-7xcex2-methyl-16xcex2-(4-chlorophenoxy)-5xcex1-androst-1-ene;
3-oxo-4-aza-7xcex2-methyl-16xcex2-(4-chlorophenoxy)-5xcex1-androstane;
3-oxo-4-aza-7xcex2-methyl-16xcex2-(3-chloro-4-methylphenoxy)-5xcex1-androstane;
3-oxo-4-aza-7xcex2-methyl-16xcex2-(4-methylphenoxy)-5xcex1-androstane;
3-oxo-4-aza-7xcex2-methyl-16xcex2-(4-methylphenoxy)-5xcex1-androst-1-ene;
3-oxo-4-aza-7xcex2-methyl-16xcex2-[4-(1-pyrrolyl)phenoxy]-5xcex1-androst-1-ene;
3-oxo-4-aza-4,7xcex2-dimethyl-16xcex2-hydroxy-5xcex1-androstane;
3-oxo-4-aza-4,7xcex2-dimethyl-16xcex2-methoxy-5xcex1-androstane;
3-oxo-4-aza-4,7xcex2-dimethyl-16xcex2-allyloxy-5xcex1-androstane;
3-oxo-4-aza-4,7xcex2-dimethyl-16xcex2-(3,3-dimethylallyloxy)-5xcex1-androstane;
3-oxo-4-aza-4,7xcex2-dimethyl-16xcex2-(n-propyloxy)-5xcex1-androstane;
3-oxo-4-aza-4,7xcex2-dimethyl-16xcex2-(iso-pentoxy)-5xcex1-androstane;
3-oxo-4-aza-4,16xcex1-dimethyl-16xcex2-hydroxy-5xcex1-androstane;
3-oxo-4-aza-4,7xcex2-dimethyl-16xcex2-ethyloxy-5xcex1-androstane;
3-oxo-4-aza-4,7xcex2-dimethyl-16xcex2-benzyloxy-5xcex1-androstane;
3-oxo-4-aza-4,7xcex2-dimethyl-16xcex1-hydroxy-5xcex1-androstane;
3-oxo-4-aza-4,7xcex2-dimethyl-16xcex2-methylthio-5xcex1-androstane;
3-oxo-4-aza-4,7xcex2-dimethyl-16xcex2-(n-propylthio)-5xcex1-androstane;
3-oxo-4-aza-4,7xcex2-dimethyl-16xcex2-fluoro-5xcex1-androstane;
3-oxo-4-aza-4,7xcex2-dimethyl-16xcex2-cyano-5xcex1-androstane;
3-oxo-4-aza-4-methyl-16xcex2-(1-hexyl)-5xcex1-androstane;
3-oxo-4-aza-4,7xcex2-dimethyl-16xcex2-(n-propyl)-5xcex1-androstane;
3-oxo-4-aza-4,7xcex2-dimethyl-16xcex2-benzyl-5xcex1-androstane;
3-oxo-4-aza-4,7xcex2-dimethyl-16xcex2-(4-chlorobenzyl)-5xcex1-androstane;
3-oxo-4-aza-4,16xcex1-dimethyl-16xcex2-methoxy-5xcex1-androstane;
3-oxo-4-aza-4,7xcex2-dimethyl-16xcex2-(4-cyanophenoxy)-5xcex1-androstane;
3-oxo-4-aza-4,7xcex2-dimethyl-16xcex2-(3-cyanophenoxy)-5xcex1-androstane;
3-oxo-4-aza-4,7xcex2-dimethyl-16xcex2-(4-nitrophenoxy)-5xcex1-androstane;
3-oxo-4-aza-4,7xcex2-dimethyl-16xcex2-(1-naphthyloxy)-5xcex1-androstane;
3-oxo-4-aza-4,7xcex2-dimethyl-16xcex2-(3-chloro-4-methylphenoxy)-5xcex1-androstane;
3-oxo-4-aza-4,7xcex2-dimethyl-16xcex2-(4-methylphenoxy)-5xcex1-androstane;
3-oxo-4-aza-4,7xcex2-dimethyl-16xcex2-(tert-butyloxy)-5xcex1-androstane;
3-oxo-4-aza-4,7xcex2-dimethyl-16xcex2-(3-methyl-1-butyloxy)-5xcex1-androstane;
3-oxo-4-aza-4,7xcex2-dimethyl-16xcex1-(n-propyloxy)-5xcex1-androstane;
3-oxo-4-aza-4,7xcex2-dimethyl-16xcex2-(4-trifluoromethylphenoxy)-5xcex1-androstane;
3-oxo-4-aza-4,7xcex2-dimethyl-16xcex2-(4-trifluoromethoxyphenoxy)-5xcex1-androstane;
3-oxo-4-aza-4,7xcex2-dimethyl-16xcex2-ethylthio-5xcex1-androstane;
3-oxo-4-aza-4,7xcex2-dimethyl-16xcex2-ethylsulfonyl-5xcex1-androstane;
3-oxo-4-aza-4,7xcex2-dimethyl-16xcex2-(4-methylsulfonylphenoxy)-5xcex1-androstane;
3-oxo-4-aza-4,7xcex2-dimethyl-16xcex2-[4-(4-tolylsulfonylamino)phenoxyl]-5xcex1-androstane;
3-oxo-4-aza-4,7xcex2-dimethyl-16xcex2-(3-pyridyloxy)-5xcex1-androstane;
3-oxo-4-aza-4,7xcex2-dimethyl-16xcex2-[(4-phenyl)phenoxy)-5xcex1-androstane;
3-oxo-4-aza-4,7xcex2-dimethyl-16xcex2-(4-fluorophenoxy)-5xcex1-androstane;
3-oxo-4-aza-4,7xcex2-dimethyl-16xcex2-(2-pyrazinyloxy)-5xcex1-androstane;
3-oxo-4-aza-4,7xcex2-dimethyl-16xcex2-[4-(5-oxazolyl)phenoxy]-5xcex1-androstane;
3-oxo-4-aza-4,7xcex2-dimethyl-16xcex2-(2-pyrimidinyloxy)-5xcex1-androstane;
3-oxo-4-aza-4,7xcex2-dimethyl-16xcex2-[4-(1-pyrryl)phenoxy]-5xcex1-androstane;
3-oxo-4-aza-4,7xcex2-dimethyl-16xcex2-(4-aminophenoxy)-5xcex1-androstane;
3-oxo-4-aza-4,7xcex2-dimethyl-16xcex2-(4-acetylaminophenoxy)-5xcex1-androstane;
3-oxo-4-aza-4,7xcex2-dimethyl-16xcex2-(4-benzoylaminophenoxy)-5xcex1-androstane;
3-oxo-4-aza-4,7xcex2-dimethyl-16xcex2-(4-chlorophenoxy)-5xcex1-androstane;
3-oxo-4-aza-4,7xcex2-dimethyl-16xcex2-(phenoxy)-5xcex1-androstane;
3-oxo-4-aza-4,7xcex2-dimethyl-16xcex2-(2-chlorophenoxy)-5xcex1-androstane;
3-oxo-4-aza-4,7xcex2-dimethyl-16xcex2-(3-chlorophenoxy)-5xcex1-androstane;
3-oxo-4-aza-4,7xcex2-dimethyl-16xcex2-(4-chlorophenoxy)-5xcex1-androst-1-ene;
3-oxo-4-aza-4,7xcex2-dimethyl-16-(4-chlorobenzylidene)-5xcex1-androstane;
3-oxo-4-aza-4,7xcex2-dimethyl-16-benzylidene-5xcex1-androstane;
3-oxo-4-aza-4,7xcex2-dimethyl-16-(4-methylbenzylidene)-5xcex1-androstane;
3-oxo-4-aza-4,7xcex2-dimethyl-16-(4-chlorobenzyl)-5xcex1-androstane;
3-oxo-4-aza-4,7xcex2-dimethyl-16-(4-methylbenzyl)-5xcex1-androstane;
3-oxo-4-aza-4,7xcex2-dimethyl-16-(3-pyridylmethyl)-5xcex1-androstane;
3-oxo-4-aza-4,7xcex2-dimethyl-16xcex1-methanesulfonyl-5xcex1-androstane;
3-oxo-4-aza-4,7xcex2-dimethyl-16xcex2-thiophenoxy-5xcex1-androstane;
3-oxo-4-aza-4,7xcex2-dimethyl-16xcex2-(4-chlorothiophenoxy)-5xcex1-androstane;
3-oxo-4-aza-4,7xcex2-dimethyl-16xcex2-(4-fluorothiophenoxy)-5xcex1-androstane;
3-oxo-4-aza-4,7xcex2-dimethyl-16xcex2-(4-methylthiophenoxy)-5xcex1-androstane;
3-oxo-4-aza-4,7xcex2-dimethyl-16xcex2-(4-methoxythiophenoxy)-5xcex1-androstane;
3-oxo-4-aza-4,7xcex2-dimethyl-16xcex2-phenylsulfinyl-5xcex1-androstane;
3-oxo-4-aza-4,7xcex2-dimethyl-16xcex2-phenylsulfonyl-5xcex1-androstane;
3-oxo-4-aza-4,7xcex2,16xcex1-trimethyl-16xcex2-(4-trifluoromethylphenoxy)-5xcex1-androstane;
3-oxo-4-aza-4,7xcex2,16xcex1-trimethyl-16xcex2-hydroxy-5xcex1-androstane;
3-oxo-4-aza-4,7xcex2,16xcex1-trimethyl-16xcex2-methoxy-5xcex1-androstane; pharmaceutically acceptable salts thereof, and analogs of the above-described compounds wherein the C1-C2 carbon-carbon bond is a double bond, and/or R1 is xe2x80x94H, and/or R2 is xe2x80x94H or methyl, where appropriate.
In another embodiment of compounds of Formula I are those further limited to those wherein the C1-C2 carbon-carbon bond is a single bond, R1 is methyl, R2 is methyl, R3 is selected from unsubstituted or substituted aryloxy, and R4 is hydrogen.
Some non-limiting examples of compounds of Formula I within this embodiment are:
3-oxo-4-aza-4,7xcex2-dimethyl-16xcex2-(4-cyanophenoxy)-5xcex1-androstane;
3-oxo-4-aza-4,7xcex2-dimethyl-16xcex2-(3-cyanophenoxy)-5xcex1-androstane;
3-oxo-4-aza-4,7xcex2-dimethyl-16xcex2-(4-nitrophenoxy)-5xcex1-androstane;
3-oxo-4-aza-4,7xcex2-dimethyl-16xcex2-(1-naphthyloxy)-5xcex1-androstane;
3-oxo-4-aza-4,7xcex2-dimethyl-16xcex2-(3-chloro-4-methylphenoxy)-5xcex1-androstane;
3-oxo-4-aza-4,7xcex2-dimethyl-16xcex2-(4-methylphenoxy)-5xcex1-androstane;
3-oxo-4-aza-4,7xcex2-dimethyl-16xcex2-(4-trifluoromethylphenoxy)-5xcex1-androstane;
3-oxo-4-aza-4,7xcex2-dimethyl-16xcex2-(4-trifluoromethoxyphenoxy)-5xcex1-androstane;
3-oxo-4-aza-4,7xcex2-dimethyl-16xcex2-(4-methylsulfonylphenoxy)-5xcex1-androstane;
3-oxo-4-aza-4,7xcex2-dimethyl-16xcex2-[4-(4-tolylsulfonylamino)phenoxy]-5xcex1-androstane;
3-oxo-4-aza-4,7xcex2-dimethyl-16xcex2-[(4-phenyl)phenoxy)-5xcex1-androstane;
3-oxo-4-aza-4,7xcex2-dimethyl-16xcex2-(4-fluorophenoxy)-5xcex1-androstane;
3-oxo-4-aza-4,7xcex2-dimethyl-16xcex2-[4-(5-oxazolyl)phenoxy]-5xcex1-androstane;
3-oxo-4-aza-4,7xcex2-dimethyl-16xcex2-[4-(1-pyrryl)phenoxy]-5xcex1-androstane;
3-oxo-4-aza-4,7xcex2-dimethyl-16xcex2-(4-aminophenoxy)-5xcex1-androstane;
3-oxo-4-aza-4,7xcex2-dimethyl-16xcex2-(4-acetylaminophenoxy)-5xcex1-androstane;
3-oxo-4-aza-4,7xcex2-dimethyl-16xcex2-(4-benzoylaminophenoxy)-5xcex1-androstane;
3-oxo-4-aza-4,7xcex2-dimethyl-16xcex2-(4-chlorophenoxy)-5xcex1-androstane;
3-oxo-4-aza-4,7xcex2-dimethyl-16xcex2-(phenoxy)-5xcex1-androstane;
3-oxo-4-aza-4,7xcex2-dimethyl-16xcex2-(2-chlorophenoxy)-5xcex1-androstane;
3-oxo-4-aza-4,7xcex2-dimethyl-16xcex2-(3-chlorophenoxy)-5xcex1-androstane;
and the pharmaceutically acceptable salts thereof.
Particularly useful compounds of structural Formula I are 3-oxo-4-aza-4,7xcex2-dimethyl-16xcex2-(4-chlorophenoxy)-5xcex1-androstane, 3-oxo-4-aza-4,7xcex2-dimethyl-16xcex2-(phenoxy)-5xcex1-androstane, and 3-oxo-4-aza-7-methyl-16xcex2-(4-methylphenoxy)-5xcex1-androst-1-ene, or pharmaceutically acceptable salts thereof.
As used herein xe2x80x9calkylxe2x80x9d is intended to include both branched-and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, e.g., methyl (Me), ethyl (Et), propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, iso-propyl (i-Pr), iso-butyl (i-Bu), tert-butyl (t-Bu), sec-butyl (s-Bu), iso-pentyl, and the like. xe2x80x9cAlkyloxyxe2x80x9d (or xe2x80x9calkoxyxe2x80x9d) represents an alkyl group having the indicated number of carbon atoms attached through an oxygen bridge, e.g., methoxy, ethoxy, propyloxy, and the like. xe2x80x9cAlkenylxe2x80x9d is intended to include hydrocarbon groups of either a straight or branched configuration with one or more carbon-carbon double bonds which may occur in any stable point along the chain, such as ethenyl, propenyl or allyl, butenyl, pentenyl, and the like. Included in this invention are all E, Z diastereomers.
The alkyl and alkenyl groups can be unsubstituted or substituted with one or more, and preferably 1-3, of:
i) halo; hydroxy; cyano; nitro; mono-, di- or trihalomethyl; oxo; hydroxysulfonyl; carboxy;
ii) hydroxyC1-6 alkyl; C1-6 alkyloxy; C1-6 alkylthio; C1-6 alkylsulfonyl; C1-6 alkyloxycarbonyl; in which the C1-6 alkyl moiety can be further substituted with 1-3 of: halo; C1-4 alkoxy; or trifluoromethyl;
iii) arylthio; aryl; aryloxy; arylsulfonyl; aryloxycarbonyl; in which the aryl moiety can be further substituted with 1-3 of: halo; C1-4 alkyl; C1-4 alkoxy; or trifluoromethyl;
iv) xe2x80x94C(O)NRbRc; xe2x80x94N(Rb)xe2x80x94C(O)xe2x80x94Rc; xe2x80x94NRbRc; where Rb and Rc are defined above; and halo is F, Cl, Br or I.
As used herein the term xe2x80x9carylxe2x80x9d, i.e., C6-10 aryl, is intended to mean phenyl or naphthyl, including 1-naphthyl and 2-naphthyl, either unsubstituted or substituted as described below.
The term xe2x80x9cheteroarylxe2x80x9d as used herein, is intended to include a 5, 6 or 7 membered heteroaromatic radical containing at least one member selected from the group consisting of: one ring oxygen atom, one ring sulfur atom, 1-4 ring nitrogen atoms, or combinations thereof; in which the heteroaryl ring can also be fused with one benzo or heteroaromatic ring. This category includes the following either unsubstituted or substituted heteroaromatic rings (as described below): pyridyl, furyl, pyrryl, thienyl, isothiazolyl, imidazolyl, benzimidazolyl, tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, quinazolinyl, isoquinolyl, benzofuryl, isobenzofuryl, benzothienyl, pyrazolyl, indolyl, isoindolyl, purinyl, carbazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxazolyl, benzthiazolyl, and benzoxazolyl. The heteroaryl ring may be attached within structural Formula I by a heteroatom, e.g., N, or carbon atom in the ring, which results in the creation of a stable structure. The heteroaryl ring can also be fused to a benzo ring.
The one to three, and more usefully one to two substituents which can be on the C6-10 aryl and heteroaryl groups named above are independently selected from:
v) halo; hydroxy; cyano; nitro; mono-, di- or trihalomethyl; mono-, di- or trihalomethoxy; C2-6 alkenyl; C3-6 cycloalkyl; formyl; hydrosulfonyl; carboxy; ureido;
vi) C1-6 alkyl; hydroxy C1-6 alkyl; C1-6 alkyloxy; C1-6 alkyloxy C1-6 alkyl; C1-6 alkylcarbonyl; C1-6 alkylsulfonyl; C1-6 alkylthio; C1-6 alkylsulfinyl; C1-6 alkylsulfonamido; C1-6 alkylarylsulfonamido; C1-6 alkyloxy-carbonyl; C1-6 alkyloxycarbonyl C1-6 alkyl; RbRcNxe2x80x94C(O)xe2x80x94C1-6 alkyl; C1-6 alkanoylamino C1-6 alkyl; aroylamino C1-6 alkyl; wherein the C1-6 alkyl moiety can be substituted with 1-3 of: halo; C1-4 alkoxy; or trifluoromethyl;
vii) aryl; aryloxy; arylcarbonyl; arylthio; arylsulfonyl; arylsulfinyl; arylsulfonamido; aryloxycarbonyl; wherein the aryl moiety can be substituted with 1-3 of: halo; C1-4 alkyl; C1-4 alkoxy; or trifluoromethyl;
viii) xe2x80x94C(O)NRbRc; xe2x80x94Oxe2x80x94C(O)xe2x80x94NRbRc; xe2x80x94N(Rb)xe2x80x94C(O)xe2x80x94Rc; xe2x80x94NRbRc; Rbxe2x80x94C(O)xe2x80x94N(Rc)xe2x80x94; where Rb and Rc are defined in (e) above; and xe2x80x94N(Rb)xe2x80x94C(O)xe2x80x94ORc, wherein this instance Rc is C1-6 alkyl or aryl; xe2x80x94N(Rb)xe2x80x94C(O)NRCRd, wherein Rd is selected from H, C1-6 alkyl, and aryl; in which said C1-6 alkyl and aryl can be substituted as described above in (e) for Rb and Rc;
ix) a heterocyclic group, which is a 5, 6 or 7 membered ring, containing at least one member selected from the group consisting of: one ring oxygen atom, one ring sulfur atom, 1-4 ring nitrogen atoms, or combinations thereof; in which the heterocyclic ring can be aromatic, unsaturated, or saturated, and wherein the heterocyclic ring can be fused with a benzo ring, and wherein said heterocyclic ring can be substituted with one to three substituents, as defined above for v), vi), vii) and viii), excluding ix) a heterocyclic group.
The fused heteroaromatic ring systems include: purine, imidazoimidazole, imidazothiazole, pyridopyrimidine, pyridopyridazine, pyrimidopyrimidine, imidazopyridazine, pyrrolopyridine, imidazo-pyridine, and the like.
The xe2x80x9cheterocyclicxe2x80x9d group includes the fully unsaturated heteroaryl rings described above and also their respective dihydro, tetrahydro and hexahydro derivatives resulting in partially unsaturated and fully saturated versions of the ring systems. Examples include: dihydroimidazolyl, dihydrooxazolyl, dihydropyridyl, tetrahydrofuryl, dihydropyrryl, tetrahydrothienyl, dihydroisothiazolyl, 1,2-dihydrobenz-imidazolyl, 1,2-dihydrotetrazolyl, 1,2-dihydropyrazinyl, 1,2-dihydro-pyrimidyl, 1,2-dihydroquinolyl, 1,2,3,4-tetrahydroisoquinolyl, 1,2,3,4-tetrahydrobenzofuryl, 1,2,3,4-tetrahydroisobenzofuryl, 1,2,3,4-tetra-hydrobenzothienyl, 1,2,3,4-tetrahydropyrazolyl, 1,2,3,4-tetrahydro-indolyl, 1,2,3,4-tetrahydroisoindolyl, 1,2,3,4-tetrahydropurinyl, 1,2,3,4-tetrahydrocarbazolyl, 1,2,3,4-tetrahydroisoxazolyl, 1,2,3,4-tetrahydro-thiazolyl, 1,2,3,4-tetrahydrooxazolyl, 1,2,3,4-tetrahydrobenzthiazolyl, and 1,2,3,4-tetrahydrobenzoxazolyl and the like.
The heterocyclic group can be substituted in the same fashion as described above for heteroaryl.
Whenever the terms xe2x80x9calkylxe2x80x9d, xe2x80x9calkenylxe2x80x9d, xe2x80x9calkyloxy (or alkoxy)xe2x80x9d, xe2x80x9carylxe2x80x9d or xe2x80x9cheteroarylxe2x80x9d, or one of their prefix roots, appear in a name of a substituent in Formula I, (e.g., aralkoxyaryloxy) they shall have the same definitions as those described above for xe2x80x9calkylxe2x80x9d, xe2x80x9calkenylxe2x80x9d, xe2x80x9calkyloxy (or alkoxy)xe2x80x9d, xe2x80x9carylxe2x80x9d and xe2x80x9cheteroarylxe2x80x9d, respectively. Designated numbers of carbon atoms (e.g., C1-10) shall refer independently to the number of carbon atoms in an alkyl or alkenyl moiety or to the alkyl or alkenyl portion of a larger substituent in which alkyl or alkenyl appears as its prefix root.
The term xe2x80x9cpharmaceutically acceptable saltxe2x80x9d is intended to include all acceptable salts such as acetate, lactobionate, benzenesulfonate, laurate, benzoate, malate, bicarbonate, maleate, bisulfate, mandelate, bitartrate, mesylate, borate, methylbromide, bromide, methylnitrate, calcium edetate, methylsulfate, camsylate, mucate, carbonate, napsylate, chloride, nitrate, clavulanate, N-methylglucamine, citrate, ammonium salt, dihydrochloride, oleate, edetate, oxalate, edisylate, pamoate (embonate), estolate, palmitate, esylate, pantothenate, fumarate, phosphate/diphosphate, gluceptate, polygalacturonate, gluconate, salicylate, glutamate, stearate, glycollylarsanilate, sulfate, hexylresorcinate, subacetate, hydrabamine, succinate, hydrobromide, tannate, hydrochloride, tartrate, hydroxynaphthoate, teoclate, iodide, tosylate, isothionate, triethiodide, lactate, panoate, valerate, and the like which can be used as a dosage form for modifying the solubility or hydrolysis characteristics or can be used in sustained release or pro-drug formulations.
The subject treated in the methods above is a female mammal, preferably a human being, diagnosed with polycystic ovary syndrome or ovarian or adrenal hyperandrogenism. Alternatively the subject treated is a human mammal, or preferably a human being, who is infertile due to irregular menstrual cycles and/or undergoing treatment with in vitro fertilization due to idiopathic infertility.
The term xe2x80x9ctherapeutically effective amountxe2x80x9d means the amount the compound of structural formula I that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician.
The term xe2x80x9ccompositionxe2x80x9d as used herein is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
By xe2x80x9cpharmaceutically acceptablexe2x80x9d it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
The terms xe2x80x9cadministration ofxe2x80x9d and or xe2x80x9cadministering axe2x80x9d compound should be understood to mean providing a compound of the invention or a prodrug of a compound of the invention to the individual in need of treatment.
The administration of the compound of structural formula I in order to practice the present methods of therapy is carried out by administering an effective amount of the compound of structural formula I to the patient in need of such treatment or prophylaxis. The need for a prophylactic administration according to the methods of the present invention is determined via the use of well known risk factors. The effective amount of an individual compound is determined, in the final analysis, by the physician in charge of the case, but depends on factors such as the exact disease to be treated, the severity of the disease and other diseases or conditions from which the patient suffers, the chosen route of administration other drugs and treatments which the patient may concomitantly require, and other factors in the physician""s judgment.
Generally, the daily dosage of the compound of structural formula I may be varied over a wide range from 0.01 to 1000 mg per adult human per day. Most preferably, dosages range from 0.1 to 100 mg/day. For oral administration, the compositions are preferably provided in the form of tablets.containing 0.01 to 1000 mg, particularly 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 3.0, 5.0, 6.0, 10.0, 15.0, 25.0, and 50.0 and 100 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
The dose may be administered in a single daily dose or the total daily dosage may be administered in divided doses of two, three or four times daily. Furthermore, when administered via intranasal routes, transdermal routes, by rectal suppositories, or through a continual intravenous solution, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
Formulations of the 5xcex1-reductase inhibitor employed in the present method for medical use comprise the compound of structural formula I together with an acceptable carrier thereof and optionally other therapeutically active ingredients. The carrier must be pharmaceutically acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient subject of the formulation.
The present invention, therefor further provides a pharmaceutical formulation comprising the compound of structural formula I together with a pharmaceutically acceptable carrier thereof.
The formulations include those suitable for oral, rectal, intravaginal, topical or parenteral (including subcutaneous, intramuscular and intravenous administration). Preferred are those suitable for oral administration.
The formulations may be presented in a unit dosage form and may be prepared by any of the methods known in the art of pharmacy. All methods include the step of bringing the active compound in association with a carrier which constitutes one or more ingredients. In general, the formulations are prepared by uniformly and intimately bringing the active compound in association with a liquid carrier, a waxy solid carrier or a finely divided solid carrier, and then, if needed, shaping the product into desired dosage form.
Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets, tablets or lozenges, each containing a predetermined amount of the active compound; as a powder or granules; or a suspension or solution in an aqueous liquid or non-aqueous liquid, e.g., a syrup, an elixir, or an emulsion.
A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active compound in a free flowing form, e.g., a powder or granules, optionally mixed with accessory ingredients, e.g., binders, lubricants, inert diluents, disintegrating agents or coloring agents. Molded tablets may be made by molding in a suitable machine a mixture of the active compound, preferably in powdered form, with a suitable carrier. Suitable binders include, without limitation, starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethyl-cellulose, polyethylene glycol, waxes and the like. Lubricants used in these dosage forms include, without limitation, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.
Oral liquid forms, such as syrups or suspensions in suitably flavored suspending or dispersing agents such as the synthetic and natural gums, for example, tragacanth, acacia, methyl cellulose and the like may be made by adding the active compound to the solution or suspension. Additional dispersing agents which may be employed include glycerin and the like.
Formulations for vaginal or rectal administration may be presented as a suppository with a conventional carrier, i.e., a base that is nontoxic and nonirritating to mucous membranes, compatible with the compound of structural formula I, and is stable in storage and does not bind or interfere with the release of the compound of structural formula I. Suitable bases include: cocoa butter (theobroma oil), polyethylene glycols (such as carbowax and polyglycols), glycol-surfactant combinations, polyoxyl 40 stearate, polyoxyethylene sorbitan fatty acid esters (such as Tween, Myrj, and Arlacel), glycerinated gelatin, and hydrogenated vegetable oils. When glycerinated gelatin suppositories are used, a preservative such as methylparaben or propylparaben may be employed.
Topical preparations containing the active drug component can be admixed with a variety of carrier materials well known in the art, such as, e.g., alcohols, aloe vera gel, allantoin, glycerine, vitamin A and E oils, mineral oil, PPG2 myristyl propionate, and the like, to form, e.g., alcoholic solutions, topical cleansers, cleansing creams, skin gels, skin lotions, and shampoos in cream or gel formulations. See, e.g., EP 0 285 382.
The compounds of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
Compounds of the present invention may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled. The compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinyl-pyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxy-ethylaspartamidephenol, or polyethylene-oxide polylysine substituted with palmitoyl residues. Furthermore, the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
Formulations suitable for parenteral administration include formulations which comprise a sterile aqueous preparation of the active compound which is preferably isotonic with the blood of the recipient. Such formulations suitably comprise a solution or suspension of a compound that is isotonic with the blood of the recipient subject. Such formulations may contain distilled water, 5% dextrose in distilled water or saline and the active compound. Often it is useful to employ a pharmaceutically and pharmacologically acceptable acid addition salt of the active compound that has appropriate solubility for the solvents employed. Useful salts include the hydrochloride isothionate and methanesulfonate salts. Useful formulations also comprise concentrated solutions or solids comprising the active compound which on dilution with an appropriate solvent give a solution suitable for parenteral administration.
The compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydro-pyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
The pharmaceutical composition and method of the present invention may further comprise other therapeutically active compounds usually applied in the treatment of the above mentioned pathological conditions, for instance: GnRH analogues, oral contraceptives, antiandrogens, clomiphene, gonadotropins, or steroids, such as prednisone, estrogens and progestins.
The composition and method of the present invention may further comprise a type 2 5xcex1-reductase inhibitor or a dual 5xcex1-reductase inhibitor. Preferred type 2 5xcex1-reductase inhibitors for use in the present composition and method include: finasteride and epristeride. A preferred dual inhibitor is: 17xcex2-N-(2,5-bis(trifluoromethyl))phenyl carbamoyl-4-aza-5xcex1-androst-1-en-3-one.
One aspect of the present invention provides a method for treating polycystic ovary syndrome comprising administering to a female mammal in need of treatment an effective amount of a compound of structural formula I.
Another aspect of the present invention provides a method of improving fertility and the response to in vitro fertilization (I.V.F.) comprising administering to a female mammal in need of treatment and effective amount of a compound of structural formula I.
In particular, when a type 2 5xcex1-reductase inhibitor or a dual 5xcex1-reductase inhibitor is employed, dosages of 0.01 to 10 mg per adult human per day are appropriate for treatment, more preferably 1 to 5 mg/day especially preferred is about 5 mg/day.
The compounds of the methods of the present invention can be administered by a variety of routes including oral, rectal, vaginal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal, and such compounds are preferably formulated prior to administration. Therefore, another embodiment of the present invention is a pharmaceutical formulation comprising an effective amount of a compound of structural formula I or a pharmaceutically acceptable salt thereof, a dual 5xcex1-reductase inhibitor, and a pharmaceutically acceptable carrier, diluent or excipient therefor.
In accordance with the method of the present invention, the individual components of the combination can be administered separately at different times during the course of therapy or concurrently in divided or single combination forms. The instant invention is therefore to be understood as embracing all such regimes of simultaneous or alternating treatment and the term xe2x80x9cadministeringxe2x80x9d is to be interpreted accordingly. It will be understood that the scope of combinations of the compounds of this invention with other agents useful for treating polycystic ovary syndrome and with other agents useful in improving fertility and the response to in vitro fertilization (I.V.F.) by employing a 5xcex1-reductase type 1 inhibitor.
The compounds of structural formula I may be prepared as described in PCT publication WO 95/11254, and are available to one of ordinary skill in the art.
The 5xcex1-reductase type 2 inhibitor finasteride that may employed this invention can be prepared as described in U.S. Pat. No. 4,760,071.